Department of Nutrition Physiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
EMBO Rep. 2021 May 5;22(5):e50766. doi: 10.15252/embr.202050766. Epub 2021 Mar 22.
SIRT7 is a NAD -dependent deacetylase that controls important aspects of metabolism, cancer, and bone formation. However, the molecular targets and functions of SIRT7 in the kidney are currently unknown. In silico analysis of kidney transcripts of the BXD murine genetic reference population revealed a positive correlation between Sirt7 and Slc12a7 mRNA expression, suggesting a link between the corresponding proteins that these transcripts encode, SIRT7, and the K-Cl cotransporter KCC4, respectively. Here, we find that protein levels and activity of heterologously expressed KCC4 are significantly modulated depending on its acetylation status in Xenopus laevis oocytes. Moreover, SIRT7 interacts with KCC4 in a NAD -dependent manner and increases its stability and activity in HEK293 cells. Interestingly, metabolic acidosis increases SIRT7 expression in kidney, as occurs with KCC4. In contrast, total SIRT7-deficient mice present lower KCC4 expression and an exacerbated metabolic acidosis than wild-type mice during an ammonium chloride challenge. Altogether, our data suggest that SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, and reveals a novel role for SIRT7 in renal physiology.
SIRT7 是一种依赖 NAD 的去乙酰化酶，可控制代谢、癌症和骨形成的重要方面。然而，SIRT7 在肾脏中的分子靶标和功能目前尚不清楚。BXD 鼠遗传参考群体的肾脏转录物的计算机分析显示，Sirt7 和 Slc12a7 mRNA 表达之间存在正相关，这表明这些转录物编码的相应蛋白质 SIRT7 和 K-Cl 共转运蛋白 KCC4 之间存在联系。在这里，我们发现 KCC4 的蛋白水平和活性在 Xenopus laevis 卵母细胞中根据其乙酰化状态显著调节。此外，SIRT7 以 NAD 依赖性方式与 KCC4 相互作用，并在 HEK293 细胞中增加其稳定性和活性。有趣的是，代谢性酸中毒会增加肾脏中的 SIRT7 表达，就像 KCC4 一样。相比之下，在氯化铵挑战期间，总 SIRT7 缺陷型小鼠的 KCC4 表达和代谢性酸中毒比野生型小鼠更严重。总的来说，我们的数据表明 SIRT7 通过去乙酰化作用与 KCC4 相互作用、稳定和调节其活性，并揭示了 SIRT7 在肾脏生理学中的新作用。
